A Systematic Review and Meta-analysis of the Diagnostic Accuracy of Nucleic Acid Amplification Tests for Tuberculous Meningitis

Abstract

The diagnosis of tuberculous meningitis (TBM) is difficult and poses a significant challenge to physicians worldwide. Recently, nucleic acid amplification (NAA) tests have shown promise for the diagnosis of TBM, although their performance has been variable. We undertook a systematic review and meta-analysis to evaluate the diagnostic accuracy of NAA tests with cerebrospinal fluid (CSF) samples against that of culture as the reference standard or a combined reference standard (CRS) for TBM. We searched the Embase, PubMed, Web of Science, and Cochrane Library databases for the relevant records. The QUADAS-2 tool was used to assess the quality of the studies. Diagnostic accuracy measures (i.e., sensitivity and specificity) were pooled with a random-effects model. All statistical analyses were performed with STATA (version 14 IC; Stata Corporation, College Station, TX, USA), Meta-DiSc (version 1.4 for Windows; Cochrane Colloquium, Barcelona, Spain), and RevMan (version 5.3; The Nordic Cochrane Centre, the Cochrane Collaboration, Copenhagen, Denmark) software. Sixty-three studies comprising 1,381 cases of confirmed TBM and 5,712 non-TBM controls were included in the final analysis. These 63 studies were divided into two groups comprising 71 data sets (43 in-house tests and 28 commercial tests) that used culture as the reference standard and 24 data sets (21 in-house tests and 3 commercial tests) that used a CRS. Studies which used a culture reference standard had better pooled summary estimates than studies which used CRS. The overall pooled estimates of sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR) of the NAA tests against culture were 82% (95% confidence interval [CI], 75 to 87%), 99% (95% CI, 98 to 99%), 58.6 (95% CI, 35.3 to 97.3), and 0.19 (95% CI, 0.14 to 0.25), respectively. The pooled sensitivity, specificity, PLR, and NLR of NAA tests against CRS were 68% (95% CI, 41 to 87%), 98% (95% CI, 95 to 99%), 36.5 (95% CI, 15.6 to 85.3), and 0.32 (95% CI, 0.15 to 0.70), respectively. The analysis has demonstrated that the diagnostic accuracy of NAA tests is currently insufficient for them to replace culture as a lone diagnostic test. NAA tests may be used in combination with culture due to the advantage of time to result and in scenarios where culture tests are not feasible. Further work to improve NAA tests would benefit from the availability of standardized reference standards and improvements to the methodology.

Low diagnostic accuracy of Xpert MTB/RIF assay for extrapulmonary tuberculosis: A multicenter surveillance

“…Given the limitations of tests for EPTB detection, Xpert MTB/RIF has been evaluated in several studies 9–15 . Although Xpert MTB/RIF assay has been validated for TB detection in sputum by authors in different countries, the efficacy of this automated molecular platform for TB detection in nonrespiratory specimens was highly variable, as its sensitivity ranged from 30% to 100% 16–26 . Furthermore, the efficacy of Xpert MTB/RIF has not been yet investigated in Iran.…”

Diagnostic accuracy of Xpert MTB/RIF for tuberculous meningitis: systematic review and meta‐analysis

“…The diagnostic accuracy of Xpert MTB/RIF for TBM has been evaluated in prior systematic reviews and meta‐analyses [54–58]. When Xpert MTB/RIF was evaluated in definite cases, the sensitivity ranged from 61 to 85% and specificity from 97% to 100% [54–58]. When Xpert MTB/RIF was evaluated versus a composite reference standard, the sensitivity ranged from 62.8% to 66% and specificity from 89% to 98.8% [54, 57].…”

“…When Xpert MTB/RIF was evaluated in definite cases, the sensitivity ranged from 61 to 85% and specificity from 97% to 100% [54–58]. When Xpert MTB/RIF was evaluated versus a composite reference standard, the sensitivity ranged from 62.8% to 66% and specificity from 89% to 98.8% [54, 57]. In most studies, CSF cultures were the gold standard; however, culture has only moderate sensitivity (30–60%) [59–61].…”

“…The analysis of 14 studies showed sensitivity of 56% (95% CI, 46–66%), specificity of 98% (95% CI, 97–99%), LR + 35.1 (95% CI, 19.0–64.6) and LR− 0.44 (95% CI, 0.33–0.60). Recently, Pormohammad et al, reported a systematic review and meta‐analysis of 28 datasets to evaluate the accuracy of commercial nucleic acid amplification tests (including Xpert MTB/RIF) for TBM [57]. Se, Sp, LR+ and LR− of commercial tests against culture were 67% (95% CI 58–75%), 99% (95% CI 98–99%), 46.1 (95% CI 28.3–75.0) and 0.33 (95% CI 0.25–0.43), respectively.…”

Comparative evaluation of IS6110 and protein antigen b PCR in cerebrospinal fluid for rapid diagnosis of tuberculous meningitis in children

“…Negi et al reported sensitivities of Pab-PCR, BACTEC, LJ medium and ZN smear to be nearly 74, 53, 47 and 35 %, respectively, in 168 patients of suspected pulmonary and extra-pulmonary TB [15]. In a recently published systematic review, the pooled sensitivity and specificity of in-house nucleic acid amplification tests were 68 % (38-88 %) and 98 % (95-100 %), respectively [20]. The use of CSF 'filtrates' rather than 'sediments' may increase the sensitivity of PCR from 53-88 % [21].…”